Irregularities of the heartbeat due to cardiac electrical dysfunction are one of the most frequent causes of mortality and morbidity in the human population. Major advances have been made recently in studying the molecular processes of cardiac electrical excitation. Despite this important progress, the mechanisms that underlie arrhythmogenic activity in patients remain only partially understood. Consequently, treatment (by drugs or non-pharmacological interventions) remains largely empirical with unpredictable outcomes in many cases. The overall objective of this project is to further our understanding of mechanisms that underlie cardiac excitation and arrhythmias, and of principles behind interventions that lead to arrhythmia termination and prevention. It is our premise that understanding of mechanisms is imperative to the development of effective treatment of arrhythmia (including new approaches such as molecular and gene therapy) and prevention of sudden death. Our approach is to study these phenomena through the use of detailed mathematical, computer models in close conjunction with experimental observations. Using computational biology, we will integrate processes from the molecular level (ion-channel structure/function) to the whole-cell, and to the multicellular cardiac tissue. The focus of this application is on action potential (AP) repolarization and its rate dependence. Specific aims are: (1)To develop the computational biology methodology for relating the molecular structure of ion channels and its dynamic conformational changes during gating to the channel kinetic properties and functioning as current carrier in the whole-cell. (2)To use the above approach to study the effects of mutations that alter the channel protein structure on whole cell electrophysiological function and rate-dependent repolarization of the AP. (3) To develop a quantitatively accurate model of the human cardiac ventricular AP based on extensive data from the normal human heart, and to study rate dependent properties of the human AP. (4) To study the properties and repolarization-dependent mechanisms of arrhythmias in the remodeled myocardium post myocardial infarction. The proposal has an important translational element, as understanding the molecular basis of channel gating and arrhythmia will assist in design of new therapies (pharmacological and molecular). Given the large interspecies differences, the development of an accurate human myocyte model based on consistent human data is essential for simulating human arrhythmias and evaluating possible therapies. Finally, myocardial infarction is a major cause of cardiac arrhythmias and sudden death, which gives this proposal a very important clinical significance. PUBLIC HEALTH RELEVANCE: An estimated 400,000 Americans die each year from erratic heart rhythms and many more are severely disabled (estimated annual fatalities worldwide is seven million). The proposed research is aimed at understanding the disease processes that cause cardiac rhythm disorders so that mechanism-based diagnosis, prevention and treatment can be developed and applied.